Measuring kidney function: the voice of Africa
Authors: Abdou Niang, Valerie A Luyckx
Journal: The Lancet Global Health (2022)

“What gets measured gets done” Margaret Chan, former director-general of WHOKidney disease is an important public health concern. Globally, kidney dysfunction—defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/1·73 m2 or albumin to creatinine ratio ≥30 mg/g—was the eighth leading risk factor for death and the eleventh leading risk factor for disability-adjusted life years (DALY) in 2019.1Levey AS Grams ME Inker LA Uses of GFR and albuminuria level in acute and chronic kidney disease.N Engl J Med. 2022; 386: 2120-2128Crossref PubMed Scopus (6) Google Scholar Data on the prevalence of kidney disease in sub-Saharan Africa are scarce, but existing data suggest that in 2019 kidney dysfunction was the eleventh and twelfth risk factor for death and DALYs, respectively.1Levey AS Grams ME Inker LA Uses of GFR and albuminuria level in acute and chronic kidney disease.N Engl J Med. 2022; 386: 2120-2128Crossref PubMed Scopus (6) Google ScholarDiagnosis and determination of the prevalence of kidney disease rely on accurate laboratory testing and estimation of GFR. A 2022 study stated that “testing for kidney disease is part of routine clinical practice for patients with acute or chronic illness”.1Levey AS Grams ME Inker LA Uses of GFR and albuminuria level in acute and chronic kidney disease.N Engl J Med. 2022; 386: 2120-2128Crossref PubMed Scopus (6) Google Scholar However, such testing is not routine in much of sub-Saharan Africa, partly because of reliance on out-of-pocket payments and partly because of a paucity of essential (and quality) diagnostic services. Furthermore, some discussions, primarily in North America, have questioned the use of race in eGFR formulae, which systematically overestimate eGFR in African American people.2Powe NR Black kidney function matters: use or misuse of race?.JAMA. 2020; 324: 737-738Crossref PubMed Scopus (71) Google Scholar Investigators have sought to improve the accuracy of eGFR formulae by eliminating race and using additional markers of kidney function such as cystatin C.3Inker LA Eneanya ND Coresh J et al.New creatinine- and cystatin C-based equations to estimate GFR without race.N Engl J Med. 2021; 385: 1737-1749Crossref PubMed Scopus (219) Google Scholar However, before this outcry in North America, studies in Africa had already drawn attention to the fact that these eGFR formulae overestimated GFR and underestimated the prevalence of kidney disease in African populations.4Bukabau JB Yayo E Gnionsahé A et al.Performance of creatinine- or cystatin C-based equations to estimate glomerular filtration rate in sub-Saharan African populations.Kidney Int. 2019; 95: 1181-1189Summary Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 5Moodley N Hariparshad S Peer F Gounden V Evaluation of the CKD-EPI creatinine based glomerular filtration rate estimating equation in Black African and Indian adults in KwaZulu-Natal, South Africa.Clin Biochem. 2018; 59: 43-49Crossref PubMed Scopus (17) Google ScholarThese facts underscore the importance of the study in The Lancet Global Health by June Fabian and colleagues,6Fabian J Kalyesubula R Mkandawire J et al.Measurement of kidney function in Malawi, South Africa, and Uganda: a multicentre cohort study.Lancet Glob Health. 2022; 10: e1159-e1169Summary Full Text Full Text PDF Scopus (2) Google Scholar which aimed to evaluate the most reliable method to estimate kidney function in sub-Saharan Africa, as a prerequisite to determining the true burden of chronic kidney disease (CKD) in Africa. The investigators compared the accuracy of ten eGFR formulae, based on serum creatinine and cystatin C, with measured GFR (mGFR) using iohexol clearance, in 2578 adults from Malawi, Uganda, and South Africa. Major strengths of this study include its size, multicentre nature, local sample analyses, complex statistical and computational analysis, and that it was conducted by Africans for Africans, with expert international collaborators. The study supports that widely used eGFR equations significantly underestimate the prevalence of CKD in the sub-Saharan African population, even more so when ethnicity coefficients were used. This study is timely, as African practitioners were starting to use the so-called race-neutral CKD-EPI 2021 formula without knowing that it does not entirely overcome the shortcomings of previous formulae. However, new eGFR equations derived from the study cohort were not better in terms of bias, precision, and accuracy compared with creatinine-based eGFR equations, especially in patients with more advanced CKD, therefore the study could not present new solutions. Consequently, the African burden of kidney disease remains largely unknown. Several important key messages emerged from this study, as follows: serum creatinine-based eGFR formulae significantly underestimate mGFR in Africans; serum creatinine, although affordable and often accessible, is a suboptimal biomarker of kidney function; cystatin C-based eGFR formulae might be superior in sub-Saharan Africa; and cystatin C is too expensive for routine practice in sub-Saharan Africa.Recognition of the weakness of eGFR formulae is not new, given the limitations of creatinine and the better, but still suboptimal, performance of cystatin C as biomarkers for GFR.7Levey AS Titan SM Powe NR Coresh J Inker LA Kidney disease, race, and GFR estimation.Clin J Am Soc Nephrol. 2020; 15: 1203-1212Crossref PubMed Scopus (86) Google Scholar All estimations of GFR are mathematical approximations.2Powe NR Black kidney function matters: use or misuse of race?.JAMA. 2020; 324: 737-738Crossref PubMed Scopus (71) Google Scholar For example, even with the widely used CKD-EPI 2009 formula,8Levey AS Stevens LA Schmid CH et al.A new equation to estimate glomerular filtration rate.Ann Intern Med. 2009; 150: 604-612Crossref PubMed Scopus (15295) Google Scholar the P30 (percentage of eGFR within 30% of the mGFR) was only 84% (ie, for an mGFR of 80 the eGFR falls between 56 and 104 ml/min/1·73 m2, with 16% of people falling outside this range).8Levey AS Stevens LA Schmid CH et al.A new equation to estimate glomerular filtration rate.Ann Intern Med. 2009; 150: 604-612Crossref PubMed Scopus (15295) Google Scholar GFR cannot be directly measured in humans, therefore there is no true gold standard.2Powe NR Black kidney function matters: use or misuse of race?.JAMA. 2020; 324: 737-738Crossref PubMed Scopus (71) Google Scholar Iohexol plasma clearance, as used by Fabian and colleagues,6Fabian J Kalyesubula R Mkandawire J et al.Measurement of kidney function in Malawi, South Africa, and Uganda: a multicentre cohort study.Lancet Glob Health. 2022; 10: e1159-e1169Summary Full Text Full Text PDF Scopus (2) Google Scholar also uses approximations and corrections, and over-estimates or under-estimates GFR under varying circumstances.9Dubourg L Lemoine S Joannard B et al.Comparison of iohexol plasma clearance formulas vs. inulin urinary clearance for measuring glomerular filtration rate.Clin Chem Lab Med. 2020; 59: 571-579Crossref PubMed Scopus (5) Google Scholar Therefore, both eGFR and mGFR are subject to substantial bias in an individual, which can have clinical consequences.The urgent need to find reliable, affordable, and scalable biomarkers to assess kidney function more accurately remains, both in Africa and beyond. The reliance on laboratory testing for diagnosis is a major weakness of kidney care globally. Recognition of the burden of CKD is not only relevant for those living with kidney disease, because CKD is also a major risk factor for cardiovascular disease. People living with CKD have high rates of comorbidities10Tonelli M Wiebe N Manns BJ et al.Comparison of the complexity of patients seen by different medical subspecialists in a universal health care system.JAMA Netw Open. 2018; 1e184852Crossref PubMed Scopus (109) Google Scholar and therefore constitute a highly vulnerable group of individuals worldwide, who remain overlooked when undiagnosed. The effect of undiagnosed CKD is probably greatest in Africa. African scientists and nephrologists must continue to work towards a better understanding of the true burden of kidney disease. “What gets measured gets done” Margaret Chan, former director-general of WHO Kidney disease is an important public health concern. Globally, kidney dysfunction—defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/1·73 m2 or albumin to creatinine ratio ≥30 mg/g—was the eighth leading risk factor for death and the eleventh leading risk factor for disability-adjusted life years (DALY) in 2019.1Levey AS Grams ME Inker LA Uses of GFR and albuminuria level in acute and chronic kidney disease.N Engl J Med. 2022; 386: 2120-2128Crossref PubMed Scopus (6) Google Scholar Data on the prevalence of kidney disease in sub-Saharan Africa are scarce, but existing data suggest that in 2019 kidney dysfunction was the eleventh and twelfth risk factor for death and DALYs, respectively.1Levey AS Grams ME Inker LA Uses of GFR and albuminuria level in acute and chronic kidney disease.N Engl J Med. 2022; 386: 2120-2128Crossref PubMed Scopus (6) Google Scholar Diagnosis and determination of the prevalence of kidney disease rely on accurate laboratory testing and estimation of GFR. A 2022 study stated that “testing for kidney disease is part of routine clinical practice for patients with acute or chronic illness”.1Levey AS Grams ME Inker LA Uses of GFR and albuminuria level in acute and chronic kidney disease.N Engl J Med. 2022; 386: 2120-2128Crossref PubMed Scopus (6) Google Scholar However, such testing is not routine in much of sub-Saharan Africa, partly because of reliance on out-of-pocket payments and partly because of a paucity of essential (and quality) diagnostic services. Furthermore, some discussions, primarily in North America, have questioned the use of race in eGFR formulae, which systematically overestimate eGFR in African American people.2Powe NR Black kidney function matters: use or misuse of race?.JAMA. 2020; 324: 737-738Crossref PubMed Scopus (71) Google Scholar Investigators have sought to improve the accuracy of eGFR formulae by eliminating race and using additional markers of kidney function such as cystatin C.3Inker LA Eneanya ND Coresh J et al.New creatinine- and cystatin C-based equations to estimate GFR without race.N Engl J Med. 2021; 385: 1737-1749Crossref PubMed Scopus (219) Google Scholar However, before this outcry in North America, studies in Africa had already drawn attention to the fact that these eGFR formulae overestimated GFR and underestimated the prevalence of kidney disease in African populations.4Bukabau JB Yayo E Gnionsahé A et al.Performance of creatinine- or cystatin C-based equations to estimate glomerular filtration rate in sub-Saharan African populations.Kidney Int. 2019; 95: 1181-1189Summary Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 5Moodley N Hariparshad S Peer F Gounden V Evaluation of the CKD-EPI creatinine based glomerular filtration rate estimating equation in Black African and Indian adults in KwaZulu-Natal, South Africa.Clin Biochem. 2018; 59: 43-49Crossref PubMed Scopus (17) Google Scholar These facts underscore the importance of the study in The Lancet Global Health by June Fabian and colleagues,6Fabian J Kalyesubula R Mkandawire J et al.Measurement of kidney function in Malawi, South Africa, and Uganda: a multicentre cohort study.Lancet Glob Health. 2022; 10: e1159-e1169Summary Full Text Full Text PDF Scopus (2) Google Scholar which aimed to evaluate the most reliable method to estimate kidney function in sub-Saharan Africa, as a prerequisite to determining the true burden of chronic kidney disease (CKD) in Africa. The investigators compared the accuracy of ten eGFR formulae, based on serum creatinine and cystatin C, with measured GFR (mGFR) using iohexol clearance, in 2578 adults from Malawi, Uganda, and South Africa. Major strengths of this study include its size, multicentre nature, local sample analyses, complex statistical and computational analysis, and that it was conducted by Africans for Africans, with expert international collaborators. The study supports that widely used eGFR equations significantly underestimate the prevalence of CKD in the sub-Saharan African population, even more so when ethnicity coefficients were used. This study is timely, as African practitioners were starting to use the so-called race-neutral CKD-EPI 2021 formula without knowing that it does not entirely overcome the shortcomings of previous formulae. However, new eGFR equations derived from the study cohort were not better in terms of bias, precision, and accuracy compared with creatinine-based eGFR equations, especially in patients with more advanced CKD, therefore the study could not present new solutions. Consequently, the African burden of kidney disease remains largely unknown. Several important key messages emerged from this study, as follows: serum creatinine-based eGFR formulae significantly underestimate mGFR in Africans; serum creatinine, although affordable and often accessible, is a suboptimal biomarker of kidney function; cystatin C-based eGFR formulae might be superior in sub-Saharan Africa; and cystatin C is too expensive for routine practice in sub-Saharan Africa. Recognition of the weakness of eGFR formulae is not new, given the limitations of creatinine and the better, but still suboptimal, performance of cystatin C as biomarkers for GFR.7Levey AS Titan SM Powe NR Coresh J Inker LA Kidney disease, race, and GFR estimation.Clin J Am Soc Nephrol. 2020; 15: 1203-1212Crossref PubMed Scopus (86) Google Scholar All estimations of GFR are mathematical approximations.2Powe NR Black kidney function matters: use or misuse of race?.JAMA. 2020; 324: 737-738Crossref PubMed Scopus (71) Google Scholar For example, even with the widely used CKD-EPI 2009 formula,8Levey AS Stevens LA Schmid CH et al.A new equation to estimate glomerular filtration rate.Ann Intern Med. 2009; 150: 604-612Crossref PubMed Scopus (15295) Google Scholar the P30 (percentage of eGFR within 30% of the mGFR) was only 84% (ie, for an mGFR of 80 the eGFR falls between 56 and 104 ml/min/1·73 m2, with 16% of people falling outside this range).8Levey AS Stevens LA Schmid CH et al.A new equation to estimate glomerular filtration rate.Ann Intern Med. 2009; 150: 604-612Crossref PubMed Scopus (15295) Google Scholar GFR cannot be directly measured in humans, therefore there is no true gold standard.2Powe NR Black kidney function matters: use or misuse of race?.JAMA. 2020; 324: 737-738Crossref PubMed Scopus (71) Google Scholar Iohexol plasma clearance, as used by Fabian and colleagues,6Fabian J Kalyesubula R Mkandawire J et al.Measurement of kidney function in Malawi, South Africa, and Uganda: a multicentre cohort study.Lancet Glob Health. 2022; 10: e1159-e1169Summary Full Text Full Text PDF Scopus (2) Google Scholar also uses approximations and corrections, and over-estimates or under-estimates GFR under varying circumstances.9Dubourg L Lemoine S Joannard B et al.Comparison of iohexol plasma clearance formulas vs. inulin urinary clearance for measuring glomerular filtration rate.Clin Chem Lab Med. 2020; 59: 571-579Crossref PubMed Scopus (5) Google Scholar Therefore, both eGFR and mGFR are subject to substantial bias in an individual, which can have clinical consequences. The urgent need to find reliable, affordable, and scalable biomarkers to assess kidney function more accurately remains, both in Africa and beyond. The reliance on laboratory testing for diagnosis is a major weakness of kidney care globally. Recognition of the burden of CKD is not only relevant for those living with kidney disease, because CKD is also a major risk factor for cardiovascular disease. People living with CKD have high rates of comorbidities10Tonelli M Wiebe N Manns BJ et al.Comparison of the complexity of patients seen by different medical subspecialists in a universal health care system.JAMA Netw Open. 2018; 1e184852Crossref PubMed Scopus (109) Google Scholar and therefore constitute a highly vulnerable group of individuals worldwide, who remain overlooked when undiagnosed. The effect of undiagnosed CKD is probably greatest in Africa. African scientists and nephrologists must continue to work towards a better understanding of the true burden of kidney disease. AN declares no competing interests. VAL declares royalties as co-editor of The Kidney and receives research funding from the Swiss Kidney Foundation, unrelated to the areas of work discussed in this Comment. Measurement of kidney function in Malawi, South Africa, and Uganda: a multicentre cohort studyEstimating GFR using serum creatinine substantially underestimates the individual and population-level burden of impaired kidney function in Africa with implications for understanding disease progression and complications, clinical care, and service provision. Scalable and affordable ways to accurately identify impaired kidney function in Africa are urgently needed. Full-Text PDF Open Access